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==Crystal structure of a Mycobacterium smegmatis transcription initiation complex with Rifampicin-resistant RNA polymerase and bound to kanglemycin A== | ==Crystal structure of a Mycobacterium smegmatis transcription initiation complex with Rifampicin-resistant RNA polymerase and bound to kanglemycin A== | ||
<StructureSection load='6dcf' size='340' side='right' caption='[[6dcf]], [[Resolution|resolution]] 3.45Å' scene=''> | <StructureSection load='6dcf' size='340' side='right'caption='[[6dcf]], [[Resolution|resolution]] 3.45Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6dcf]] is a 9 chain structure with sequence from [http://en.wikipedia.org/wiki/ | <table><tr><td colspan='2'>[[6dcf]] is a 9 chain structure with sequence from [http://en.wikipedia.org/wiki/Mycs2 Mycs2]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6DCF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6DCF FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GLU:GLUTAMIC+ACID'>GLU</scene>, <scene name='pdbligand=KNG:Kanglemycin+A'>KNG</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GLU:GLUTAMIC+ACID'>GLU</scene>, <scene name='pdbligand=KNG:Kanglemycin+A'>KNG</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">rbpA, MSMEG_3858, MSMEI_3768 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=246196 MYCS2]), rpoB, MSMEG_1367, MSMEI_1328 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=246196 MYCS2]), sigA, MSMEG_2758 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=246196 MYCS2])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/DNA-directed_RNA_polymerase DNA-directed RNA polymerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.6 2.7.7.6] </span></td></tr> | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/DNA-directed_RNA_polymerase DNA-directed RNA polymerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.6 2.7.7.6] </span></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6dcf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dcf OCA], [http://pdbe.org/6dcf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6dcf RCSB], [http://www.ebi.ac.uk/pdbsum/6dcf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6dcf ProSAT]</span></td></tr> | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6dcf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dcf OCA], [http://pdbe.org/6dcf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6dcf RCSB], [http://www.ebi.ac.uk/pdbsum/6dcf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6dcf ProSAT]</span></td></tr> | ||
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== Function == | == Function == | ||
[[http://www.uniprot.org/uniprot/A0QW02_MYCS2 A0QW02_MYCS2]] Sigma factors are initiation factors that promote the attachment of RNA polymerase to specific initiation sites and are then released. This sigma factor is the primary sigma factor during exponential growth.[SAAS:SAAS00535554] [[http://www.uniprot.org/uniprot/RPOB_MYCS2 RPOB_MYCS2]] DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. This subunit often mutates to generate rifampicin (Rif) resistance. Interaction with RbpA partially restores Rif-inhibited transcription; once the subunit is Rif-resistant however RbpA no longer stimulates transcription.[HAMAP-Rule:MF_01321]<ref>PMID:19926651</ref> [[http://www.uniprot.org/uniprot/RPOA_MYCS2 RPOA_MYCS2]] DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates.[HAMAP-Rule:MF_00059]<ref>PMID:19926651</ref> [[http://www.uniprot.org/uniprot/RBPA_MYCS2 RBPA_MYCS2]] Binds to RNA polymerase (RNAP), probably stimulating transcriptions from principal, but not alternative sigma factor promoters (By similarity). Partially restores transcription in the presence of rifampicin (Rif) in vitro; overexpression leads to an increase in the Rif tolerance in vivo, with smaller colonies. Seems to act by removing Rif from its binding site and preventing its further binding. No longer stimulates transcription in Rif-resistant RNA polymerase (with mutations in rpoB).<ref>PMID:19926651</ref> <ref>PMID:21415119</ref> [[http://www.uniprot.org/uniprot/RPOC_MYCS2 RPOC_MYCS2]] DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates.[HAMAP-Rule:MF_01322]<ref>PMID:19926651</ref> [[http://www.uniprot.org/uniprot/RPOZ_MYCS2 RPOZ_MYCS2]] Promotes RNA polymerase assembly. Latches the N- and C-terminal regions of the beta' subunit thereby facilitating its interaction with the beta and alpha subunits.[HAMAP-Rule:MF_00366]<ref>PMID:19926651</ref> | [[http://www.uniprot.org/uniprot/A0QW02_MYCS2 A0QW02_MYCS2]] Sigma factors are initiation factors that promote the attachment of RNA polymerase to specific initiation sites and are then released. This sigma factor is the primary sigma factor during exponential growth.[SAAS:SAAS00535554] [[http://www.uniprot.org/uniprot/RPOB_MYCS2 RPOB_MYCS2]] DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. This subunit often mutates to generate rifampicin (Rif) resistance. Interaction with RbpA partially restores Rif-inhibited transcription; once the subunit is Rif-resistant however RbpA no longer stimulates transcription.[HAMAP-Rule:MF_01321]<ref>PMID:19926651</ref> [[http://www.uniprot.org/uniprot/RPOA_MYCS2 RPOA_MYCS2]] DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates.[HAMAP-Rule:MF_00059]<ref>PMID:19926651</ref> [[http://www.uniprot.org/uniprot/RBPA_MYCS2 RBPA_MYCS2]] Binds to RNA polymerase (RNAP), probably stimulating transcriptions from principal, but not alternative sigma factor promoters (By similarity). Partially restores transcription in the presence of rifampicin (Rif) in vitro; overexpression leads to an increase in the Rif tolerance in vivo, with smaller colonies. Seems to act by removing Rif from its binding site and preventing its further binding. No longer stimulates transcription in Rif-resistant RNA polymerase (with mutations in rpoB).<ref>PMID:19926651</ref> <ref>PMID:21415119</ref> [[http://www.uniprot.org/uniprot/RPOC_MYCS2 RPOC_MYCS2]] DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates.[HAMAP-Rule:MF_01322]<ref>PMID:19926651</ref> [[http://www.uniprot.org/uniprot/RPOZ_MYCS2 RPOZ_MYCS2]] Promotes RNA polymerase assembly. Latches the N- and C-terminal regions of the beta' subunit thereby facilitating its interaction with the beta and alpha subunits.[HAMAP-Rule:MF_00366]<ref>PMID:19926651</ref> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Rifamycin antibiotics (Rifs) target bacterial RNA polymerases (RNAPs) and are widely used to treat infections including tuberculosis. The utility of these compounds is threatened by the increasing incidence of resistance (Rif(R)). As resistance mechanisms found in clinical settings may also occur in natural environments, here we postulated that bacteria could have evolved to produce rifamycin congeners active against clinically relevant resistance phenotypes. We survey soil metagenomes and identify a tailoring enzyme-rich family of gene clusters encoding biosynthesis of rifamycin congeners (kanglemycins, Kangs) with potent in vivo and in vitro activity against the most common clinically relevant Rif(R) mutations. Our structural and mechanistic analyses reveal the basis for Kang inhibition of Rif(R) RNAP. Unlike Rifs, Kangs function through a mechanism that includes interfering with 5'-initiating substrate binding. Our results suggest that examining soil microbiomes for new analogues of clinically used antibiotics may uncover metabolites capable of circumventing clinically important resistance mechanisms. | |||
Rifamycin congeners kanglemycins are active against rifampicin-resistant bacteria via a distinct mechanism.,Peek J, Lilic M, Montiel D, Milshteyn A, Woodworth I, Biggins JB, Ternei MA, Calle PY, Danziger M, Warrier T, Saito K, Braffman N, Fay A, Glickman MS, Darst SA, Campbell EA, Brady SF Nat Commun. 2018 Oct 8;9(1):4147. doi: 10.1038/s41467-018-06587-2. PMID:30297823<ref>PMID:30297823</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6dcf" style="background-color:#fffaf0;"></div> | |||
== References == | == References == | ||
<references/> | <references/> | ||
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</StructureSection> | </StructureSection> | ||
[[Category: DNA-directed RNA polymerase]] | [[Category: DNA-directed RNA polymerase]] | ||
[[Category: Large Structures]] | |||
[[Category: Mycs2]] | |||
[[Category: Campbell, E A]] | [[Category: Campbell, E A]] | ||
[[Category: Darst, S A]] | [[Category: Darst, S A]] | ||
Revision as of 11:21, 20 March 2019
Crystal structure of a Mycobacterium smegmatis transcription initiation complex with Rifampicin-resistant RNA polymerase and bound to kanglemycin ACrystal structure of a Mycobacterium smegmatis transcription initiation complex with Rifampicin-resistant RNA polymerase and bound to kanglemycin A
Structural highlights
Function[A0QW02_MYCS2] Sigma factors are initiation factors that promote the attachment of RNA polymerase to specific initiation sites and are then released. This sigma factor is the primary sigma factor during exponential growth.[SAAS:SAAS00535554] [RPOB_MYCS2] DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. This subunit often mutates to generate rifampicin (Rif) resistance. Interaction with RbpA partially restores Rif-inhibited transcription; once the subunit is Rif-resistant however RbpA no longer stimulates transcription.[HAMAP-Rule:MF_01321][1] [RPOA_MYCS2] DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates.[HAMAP-Rule:MF_00059][2] [RBPA_MYCS2] Binds to RNA polymerase (RNAP), probably stimulating transcriptions from principal, but not alternative sigma factor promoters (By similarity). Partially restores transcription in the presence of rifampicin (Rif) in vitro; overexpression leads to an increase in the Rif tolerance in vivo, with smaller colonies. Seems to act by removing Rif from its binding site and preventing its further binding. No longer stimulates transcription in Rif-resistant RNA polymerase (with mutations in rpoB).[3] [4] [RPOC_MYCS2] DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates.[HAMAP-Rule:MF_01322][5] [RPOZ_MYCS2] Promotes RNA polymerase assembly. Latches the N- and C-terminal regions of the beta' subunit thereby facilitating its interaction with the beta and alpha subunits.[HAMAP-Rule:MF_00366][6] Publication Abstract from PubMedRifamycin antibiotics (Rifs) target bacterial RNA polymerases (RNAPs) and are widely used to treat infections including tuberculosis. The utility of these compounds is threatened by the increasing incidence of resistance (Rif(R)). As resistance mechanisms found in clinical settings may also occur in natural environments, here we postulated that bacteria could have evolved to produce rifamycin congeners active against clinically relevant resistance phenotypes. We survey soil metagenomes and identify a tailoring enzyme-rich family of gene clusters encoding biosynthesis of rifamycin congeners (kanglemycins, Kangs) with potent in vivo and in vitro activity against the most common clinically relevant Rif(R) mutations. Our structural and mechanistic analyses reveal the basis for Kang inhibition of Rif(R) RNAP. Unlike Rifs, Kangs function through a mechanism that includes interfering with 5'-initiating substrate binding. Our results suggest that examining soil microbiomes for new analogues of clinically used antibiotics may uncover metabolites capable of circumventing clinically important resistance mechanisms. Rifamycin congeners kanglemycins are active against rifampicin-resistant bacteria via a distinct mechanism.,Peek J, Lilic M, Montiel D, Milshteyn A, Woodworth I, Biggins JB, Ternei MA, Calle PY, Danziger M, Warrier T, Saito K, Braffman N, Fay A, Glickman MS, Darst SA, Campbell EA, Brady SF Nat Commun. 2018 Oct 8;9(1):4147. doi: 10.1038/s41467-018-06587-2. PMID:30297823[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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